Injection apparatus and special needle for making an injection at a predetermined depth in the skin

ABSTRACT

An injection apparatus for making an injection at a predetermined depth in skin comprises: a skin positioning member, an injection needle ( 610 ), and means guiding the injection needle for movement from a parking position above the skin beside said skin positioning member to slide beneath said skin positioning member to an injection position; wherein: the tip ( 620 ) of the injection needle is closer to the longitudinal axis of the shaft portion ( 650 ) than is the outside of the shaft portion ( 650 ) and/or the length of the lumen opening ( 625 ) of the needle is in a range from 5 to 15 times the diameter of the shaft ( 650 ) of the needle. An injection needle wherein the length of the lumen opening ( 625 ) of the needle is in a range from 5 to 15 times the diameter of the shaft ( 650 ) of the needle.

This application is the U.S. national phase of International ApplicationNo. PCT/EP2008/060664 filed 14 Aug. 2008 which designated the U.S. andclaims priority to GB Application No. 0716159.9 filed 17 Aug. 2007, theentire contents of each of which are hereby incorporated by reference.

The present invention relates to an injection apparatus and to a methodof injection.

Cutaneous injection is used in a number of applications. It isadvantageous to inject vaccines into the skin as antigen which is thenreleased into other tissues over a period of time, promoting theresponse by antibodies and T-cells. Assay sensors may also be injectedinto the skin, where they can be interrogated optically through theskin. Such assays are described for example in WO 00/02048 and WO02/30275. They may in particular be useful for glucose monitoring indiabetes. Cutaneous injection is also used cosmetically in wrinklefilling.

The depth at which material is injected is important, as it determinesthe layer of the skin in which the material will be deposited. The skinconsists of two principal layers: the epidermis (upper layer) and thedermis (lower layer), with an overall thickness of 1.5 to 2 mm. Theepidermis is overlaid by the stratum corneum, a layer of dead cellsapproximately 10 to 25 μm thick. The upper cells of the stratum corneumare continuously worn away. The epidermis and dermis are separated bythe basement membrane at a depth of approximately 150 μm. The cells atthe top of the epidermis progressively die and form the base of thestratum corneum, whilst the basement membrane generates new cells at thebase of the epidermis. The dermis is vasculised, whereas the epidermisis not.

The fluorophores commonly used in the competition assays referred toabove are illuminated transdermally with blue or green light, which hasa low penetration depth. Melanin, which absorbs UV and visibleradiation, is produced by the basement membrane and transferred upwardsinto the epidermis to protect the skin from UV radiation. This melaninabsorbs blue and green illumination used to interrogate the sensors andthe resulting fluorescence, and accordingly penetration through the skinis poor. Scattering in the skin and absorption of light by bloodcontributes to this effect. Therefore, the deeper the sensors arepositioned in the skin, the weaker the fluorescence detection will be.Accordingly, for optimum sensitivity of the assay, the sensors should beas close to the skin surface as possible.

However, there are disadvantages associated with positioning the reagentparticles within the epidermis or basement membrane. In particular, theconcentrations of glucose within these layers may not correlate with theblood glucose concentration which the assay is attempting to measure.This is because the epidermis is not vasculised, and the basementmembrane uses glucose in the production of epidermal cells which affectsits glucose concentration. By contrast, the concentration of glucose inthe interstitial fluid of the dermis is expected to correlate with bloodglucose concentration. Further, if the reagent particles were positionedin the epidermis, they would move towards the skin surface as theepidermal cells were renewed. Glucose concentration in the epidermis isknown to decrease towards the skin surface (and is zero at the stratumcorneum). This will lead to an erroneous glucose estimate. Particlesinjected into the dermis, on the other hand, will be retainedpermanently, as seen in a conventional tattoo.

In the light of these considerations, the optimum location for assayreagent particles is directly underneath the basement membrane, at thetop of the dermis.

In other assays, it may be desirable for sensor particles to bedeposited in the epidermis so that they will be expelled from the bodyover time (WO 02/30275). Shallow injection may be achieved using anarray of short needles coated with material to be injected. However,when injection is carried out with an array of this type material isdeposited at every depth from the skin surface to the maximumpenetration depth of the needle.

An apparatus or method that provides injection to a pre-determined depthis consequently desirable.

An apparatus and method for injection at a desired distance below thesurface of the skin are described in WO03/072172. This documentdescribes an injection apparatus having a skin positioning member whichlies or is moveable to lie above or below the surrounding area of skin,and means for inserting a needle parallel to the skin positioningmember.

International standard nomenclature for needle point geometry isdescribed in ISO7864.

Injection needle types such as a lancet type or trocar type needle areknown. Examples of such injection needle types are shown in FIGS. 1 and2. An injection needle is generally formed from tubing having a lumen(315) and a shaft (310), and a point (325) is formed at the distal endof the needle by cutting across the tubing transversely to itslongitudinal axis (305) to form at least one bevel. A lancet type needle(FIG. 1) is formed by making a primary bevel 320 at an angle α to thelongitudinal axis 305 then making secondary bevels (330) by increasingthe grinding angle α and rotating the needle with respect to thegrinding stone about the longitudinal axis of the needle. The twosecondary bevels are formed with equal and opposite rotations of theneedle about its longitudinal axis with respect to the grinding stone.The rotation angles used for the secondary bevels may be altereddepending on the intended use of the needle and are less than 90° withrespect to the primary bevel. Typically the rotation with respect to theprimary bevel is 55°. A trocar type needle (FIG. 2) may be formed bymaking three grindings to the needle; the first forms the primary bevel(420), as described above, and the secondary bevels (440) are formed ata 120° rotational angle to each other and to the primary bevel.Furthermore, the grinding angle with respect to the longitudinal axis ofthe secondary bevels is steeper than the grinding angle α for theprimary bevel. The secondary bevels may result in a tip being formed ata position (450) along the radius of the cross-section of the needleperpendicular to the longitudinal axis which lies between the outside ofthe lumen and the outside of the shaft.

The angles of the primary bevel and of the secondary bevels (if any)with respect to the longitudinal axis together determine the length ofthe point of the needle, which is defined as the length 325 from thevery tip of the needle to the heel (the edge formed by the bevel surfacemeeting the outer surface of the shaft on the opposite side from thetip; 335).

In a first aspect, the present invention provides an injection apparatusfor making an injection at a predetermined depth in skin comprising:

-   a skin positioning member for positioning on a patch of skin within    an area of skin to hold the patch of skin in a defined position,-   an injection needle comprising a point having a tip at a distal end    thereof and a shaft portion immediately proximal to said point, the    shaft portion having a longitudinal axis, and means guiding said    injection needle for movement from a parking position above the skin    beside said skin positioning member to slide beneath said skin    positioning member to an injection position in which the distal end    of the needle lies at a predetermined distance below said skin    positioning member;    wherein:-   the tip of the injection needle is closer to the longitudinal axis    of the shaft portion than is the outside of the shaft portion.

We have found that, in a device as described in WO03/072172, it issometimes difficult to insert the needle to the correct depth in theskin due to the shape of the point of the needle. This is particularlyfound to be a problem with needles having a larger diameter, such asthose used for injecting sensor particles as described above. Thediameter of needles for such applications may be large compared with thethickness of the skin (1.5 mm). Referring to FIG. 3, using aconventional lancet-type point needle (300), the sensor (360) may beinjected too deeply when using the needle with the primary bevel facingaway from the skin surface (370) (FIG. 3b ), or the needle may slideover the skin without penetrating the surface when using the needle withthe primary bevel facing towards the skin surface (370) (FIG. 3a ). Itis therefore necessary to solve this problem in order to ensure that aneedle may reliably be inserted to the required depth in the skin.

From the description of the known lancet and trocar type needles, it maybe seen that known patterns of grinding in some cases do and in somecases do not result in the needle tip being closer to the axis of thelumen than is the outside wall of the surface of the needle. Where thegrinding does not provide this feature, we have found that modificationof the needle point in order that the tip of the injection needle iscloser to the longitudinal axis of the shaft portion than is the outsideof the shaft portion allows for more reliable insertion of the needle tothe required depth in skin.

Suitably, the needle tip may be made closer to the longitudinal axis ofthe shaft portion than is the outside of the shaft portion by modifyinga lancet-type needle of the type described above by bending the tip ofthe needle towards the longitudinal axis of the shaft. Suitably, thebending of the tip of the needle may be done before or after theformation of the secondary bevels of the point are carried out.Preferably, however, the bending of the tip is carried out before thesecondary bevels are formed in order to avoid producing a sharp edge atthe tip of the needle that may damage the sensor to be injected.

Alternatively, the needle tip may be made closer to the longitudinalaxis of the shaft portion than is the outside of the shaft portion byproviding a suitable grinding or combination of grindings at the needletip. Suitably, a trocar-type needle of the type described above may beused. Such a trocar-type needle may be provided with at least onefurther grinding at the tip of the needle which, without changing theposition of the needle tip relative to the longitudinal axis of theneedle, provides a more gradual slope from the outside of the shafttowards the tip on the back of the needle (the side opposite the heel).

The inventors have proposed that the incorrect positioning of theinjected material resulting from using the needle with the primary bevelfacing away from the surface of the skin (as in FIG. 3b ) may be due tobending of the needle during insertion into the skin caused by acomponent of the reaction force from the skin acting on at least theprimary bevel perpendicular to the injection path. This bending resultsin deviation of the needle from the intended injection path. Wheninjecting material such as a solid sensor particle, it is particularlyimportant that the injection is made at the correct depth to ensurecorrect placement of the sensor in the skin, and a large gauge needlemust be used in order to accommodate the sensor within the lumen. Thus,the inventors have devised a needle in which the component of thereaction force acting perpendicular to the injection path is reducedcompared with standard designs of injection needle.

Accordingly, the present invention provides in a second aspect aninjection apparatus for making an injection at a predetermined depth inskin comprising:

-   a skin positioning member for positioning on a patch of skin within    an area of skin to hold the patch of skin in a defined position,-   an injection needle comprising a tip, at least one bevel and a heel    together forming a point at a distal end thereof, and a shaft    portion immediately proximal of said heel having a longitudinal    axis, including a lumen extending along the longitudinal axis,    wherein the at least one bevel is formed between said tip and said    heel such that a lumen opening is defined extending from the tip to    a proximal end of the lumen opening located distal of the heel; and-   means guiding said injection needle for movement from a parking    position above the skin beside said skin positioning member to slide    beneath said skin positioning member to an injection position in    which the distal end of the needle lies at a predetermined distance    below said skin positioning member;    wherein:-   the length of the lumen opening of the needle is in a range from 5    to 15 times the diameter of the shaft of the needle. For example,    the length of the lumen opening of the needle may be in the range    from 8 to 12 times the diameter of the shaft of the needle, such as    ten times the diameter of the shaft of the needle.

The present invention further provides in a third aspect an injectionneedle comprising a tip, at least one bevel and a heel together forminga point at a distal end thereof, and a shaft portion immediatelyproximal of said heel having a longitudinal axis, including a lumenextending along the longitudinal axis, wherein the at least one bevel isformed between said tip and said heel such that the lumen opening isdefined from the tip to a proximal end of the lumen opening locateddistal of the heel,

-   characterised in that the length of the lumen opening of the needle    is in a range from 5 to 15 times the diameter of the shaft of the    needle. For example, the length of the lumen opening of the needle    may be in the range from 8 to 12 times the diameter of the shaft of    the needle, such as ten times the diameter of the shaft of the    needle.

Preferably, the needles of the second and third aspects of the inventionhave a shaft diameter of from 0.5 mm to 1.5 mm, for example 0.8 to 1.3mm or 1.0 to 1.2 mm, particularly preferably 1.1 mm. Where the shaftdiameter is 1.1 mm, the length of the lumen opening may be from 5.5 mmto 16.5 mm, for example 8.8 to 13.2 mm, such as 11 mm.

Preferably, at least a part of the point of a needle of the second orthird aspect of the invention is formed substantially parallel to thelongitudinal axis of the needle, and most preferably, at least half ofthe point length is formed parallel to the longitudinal axis of theneedle. This results in that part of the point having a part-cylindricalform with a constant cross-section. Preferably, the distanceperpendicular to the longitudinal axis of the needle from the tip to thebevel face at the part-cylindrical point section is at least 50% of thediameter of the shaft of the needle, such as 60% or 70%. Preferably, thepart-cylinder has a semi-circular cross-section, i.e. is ahemi-cylinder. Preferably, the section of the point distal of thepart-cylindrical point section is shaped into a desired needle tipgeometry, suitably a lancet or trocar tip geometry, and that geometrymay suitably be modified in accordance with the needles described in thefirst aspect of the invention. Preferably, the section of the pointimmediately distal of the heel and proximal of the part-cylindricalpoint section forms a further bevel at an angle to the longitudinalaxis, suitably 8 to 12°, such as 10°. Suitably, the transition betweenthe part-cylindrical point section and the further bevel may be arounded transition or a chamfered transition.

Suitably, the needle tip may be bent or ground or otherwise shaped suchthat the tip is closer to the longitudinal axis of the needle, asdescribed previously.

An additional benefit of using a needle according to the second or thirdaspect of the invention is that, when using needles having an outerdiameter that is a significant proportion of the thickness of the dermis(around 1.5 mm) for intradermal injection, there is a reduction of thestress and lesions in the dermis caused by the insertion of the needlecompared with that caused by a conventional needle. The stress andlesions may be further reduced if the full diameter of the needle tubeis introduced only a short distance, such as 1 mm, into the skin.

Preferably, the apparatus further comprises means for attaching saidskin positioning member to the skin.

Preferably, said skin positioning member is arranged such that at leasta portion of said skin positioning member lies or is moveable to lieabove or below said area of skin such that at least a part of said patchof skin is held elevated above or depressed below said area of skin.

Preferably, the needle is guided for movement of the distal end of theneedle at a constant distance below the surface of a lifted patch ofskin attached to the skin positioning member. This will ensure that theinjection depth is not dependent on the precise distance over which theneedle point is moved, as would be the case if the needle movedobliquely with respect to the skin positioning member. Preferably, theskin positioning member holds the surface of the lifted area of skinflat (planar). The movement of the needle is then preferably parallel tothe skin positioning member surface.

The skin positioning member preferably has adhesive thereon to securethe patch of skin to the skin positioning member. Alternatively, theskin positioning member may be porous or provided with bores throughwhich vacuum may be applied to hold the skin to the skin positioningmember. In an alternative embodiment, the skin positioning member may bepressed against the patch of skin to depress the patch of skin. Suchdepression of the patch of skin may be such that the patch of skin liesobliquely slanted with respect to the natural orientation, allowing theneedle to penetrate therebelow from its edge.

The skin positioning member may be plate-like, or may form the surfaceof a non-plate-like member, for example a cone, a pyramid, a triangularprism or a hemisphere.

Preferably, said skin positioning member is moveable between a firstposition in which it lies on said area of skin and a second position inwhich at least a portion of said skin positioning member is elevatedabove or depressed below said area of skin with said patch of skin.However, the skin positioning member may be fixed in a position elevatedabove the surface of the skin and the skin may be drawn up to the skinpositioning member by the application of vacuum and retained thereagainst the skin positioning member by vacuum or by adhesive asdescribed, or the skin positioning member may be fixed in a positiondepressed below said area of skin.

Preferably, means are provided for tilting said skin positioning memberto elevate an edge thereof with said patch of skin attached thereto tolift said patch of skin. Alternatively, however, the whole skinpositioning member may be elevated, with or without some tilting also,to raise the patch of skin. To conveniently provide for the tiltingmovement, said skin positioning member is preferably carried by asupport structure to which the skin positioning member may be hinged atone edge of the skin positioning member.

The skin positioning member may be moved using by the interaction of oneor more cam followers carried by the skin positioning member eachengaging a cam groove in a cam plate which is mounted for slidingmovement with respect to the skin positioning member.

The injection needle preferably is guided for movement using one or morecam followers attached to the needle each engaging in a cam groove in acam plate mounted for sliding movement with respect to the needle andthe same cam plate may control the movement of the skin positioningmember and of the injection needle.

The apparatus may comprise a lower portion which is left on the skinafter injection to define or mark the injection site and an upperportion containing the injection needle which is detachable afterinjection. Said upper portion may further include said skin positioningmember although this could be mounted to the lower portion so that it isleft behind when the upper portion is removed. It could then eitherremain as part of the lower portion or be removed separately. If it weremade transparent, it could remain covering the injection site andoptical interrogation of an injected sensor could be made therethrough.

The predetermined depth at which injection is made using the apparatusis suitably in the range of 100 μm to 2 mm and may be fixed duringmanufacture or may be user adjustable.

Said injection needle is preferably carried by a syringe comprising achamber for injectable material and means for dispensing said materialthrough said needle. The syringe may contain as said injectable materialparticles to be injected and may contain in separate compartments saidparticles to be injected and a liquid for suspending the particles.

As indicated above, desirably the particles are assay sensor particlescontaining assay reagents. However, the injectable material in thesyringe may alternatively be a medicament and may be an antigen for usein an immunisation. The injectable material may be in the form of aliquid, paste, emulsion, a single implant or sensor particle, aplurality of implants or sensor particles, or a suspension of implantsor sensor particles in a liquid.

The invention includes in a fourth aspect injection apparatus comprisinga housing containing an injection needle comprising a point having a tipat a distal end thereof and a shaft portion immediately proximal to saidpoint having a longitudinal axis and mounted for guided movement from aparked position to an operative position, a detachable marker unitmounted to said housing and so positioned that said needle passestherethrough to reach said operative position, and means for securingsaid marker unit at an injection site prior to the making of aninjection, wherein said tip of the injection needle is closer to thelongitudinal axis of the shaft portion than is the outside of the shaftportion of the needle, and whereby said apparatus can in use bepositioned at an injection site, said marker unit can be secured at saidinjection site, said needle can be moved to said operative position tomake an injection and said housing can be removed leaving said markerunit at the injection site to mark the position thereof.

Said marker unit may comprise a plate having an aperture therein throughwhich the needle passes in use. Said aperture preferably has a maximumdimension of 2 mm or less. Apparatus according to this fourth aspect ofthe invention may have all or any of the features described above inconnection with the first aspect of the invention.

In a fifth aspect, the present invention provides an injection apparatuscomprising a housing containing:

-   an injection needle comprising a tip, at least one bevel and a heel    together forming a point at a distal end thereof, and a shaft    portion immediately proximal of said heel having a longitudinal    axis, including a lumen extending along the longitudinal axis,    wherein the at least one bevel is formed between said tip and said    heel such that a lumen opening is defined from the tip to a proximal    end of the lumen opening located distal of the heel, said injection    needle being mounted for guided movement from a parked position to    an operative position;-   a detachable marker unit mounted to said housing and so positioned    that said needle passes therethrough to reach said operative    position; and-   means for securing said marker unit at an injection site prior to    the making of an injection; wherein the length of the lumen opening    of the needle is in a range from 5 to 15 times the diameter of the    shaft of the needle, and-   whereby said apparatus can in use be positioned at an injection    site, said marker unit can be secured at said injection site, said    needle can be moved to said operative position to make an injection    and said housing can be removed leaving said marker unit at the    injection site to mark the position thereof.

Said marker unit may comprise a plate having an aperture therein throughwhich the needle passes in use. Said aperture preferably has a maximumdimension of 2 mm or less. Apparatus according to the fourth and fifthaspects of the invention may have all or any of the features describedabove in connection with the first, second or third aspects of theinvention.

The invention further includes a method of fixed-depth cutaneousinjection comprising: holding the surface of a patch of skin in adefined position against the surface of a skin positioning member andguiding an injection needle beneath the skin positioning member to bringa discharge opening of the injection needle to a predefined locationbeneath the skin positioning member, wherein the injection needlecomprises a point having a tip at a distal end thereof and a shaftportion immediately proximal to said point having a longitudinal axis,and wherein the tip of the needle is closer to the longitudinal axis ofthe shaft portion than is the outside of the shaft portion. This methodmay be carried out using apparatus according to either or both of thefirst and fourth aspects of the invention.

The invention includes a second method of fixed-depth cutaneousinjection comprising: holding the surface of a patch of skin in adefined position against the surface of a skin positioning member andguiding an injection needle beneath the skin positioning member to bringa discharge opening of the injection needle to a predefined locationbeneath the skin positioning member, wherein the injection needlecomprises a tip, at least one bevel and a heel together forming a pointat a distal end thereof, and a shaft portion immediately proximal ofsaid heel having a longitudinal axis, including a lumen extending alongthe longitudinal axis, wherein the at least one bevel is formed betweensaid tip and said heel such that the lumen opening is defined from thetip to a proximal end of the lumen opening located distal of the heel,and wherein the length of the lumen opening of the needle is in a rangefrom 5 to 15 times the diameter of the shaft of the needle. This methodmay be carried out using apparatus according to either or both of thesecond and fifth aspects of the invention.

Suitably, these methods can be carried out by a patient onhimself/herself without the need for assistance from medical personnel.

Preferably, said injection needle is guided such that not more than 1 mmof the length of the shaft portion of the needle is inserted beneath thesurface of the skin.

The invention will be further described with reference to the preferredembodiments shown in the accompanying drawings, in which:

FIG. 1 shows an example of a known lancet-type injection needle. View(a) shows the primary bevel face of the needle, view (b) shows theneedle rotated by 90° about its longitudinal axis compared with view(a), and view (c) shows the needle rotated about its longitudinal axisby 180° compared with view (a).

FIG. 2 shows an example of a needle for use in the apparatus of thepresent invention. View (a) shows the primary bevel face of the needle,view (b) shows the needle rotated by 90° about its longitudinal axiscompared with view (a), and view (c) shows the needle rotated about itslongitudinal axis by 180° compared with view (a).

FIG. 3 shows the resulting position of a sensor injected using theprimary bevel of the needle (a) facing towards the skin, and (b) facingaway from the skin.

FIG. 4 shows a vertical cross section through an illustrative embodimentof the invention;

FIG. 5 shows the same embodiment in perspective view;

FIG. 6 shows the same perspective view but with some upper componentsremoved;

FIG. 7 is an enlarged view of the syringe component of the apparatus asshown in FIG. 4;

FIG. 8 is a plan view of the apparatus as shown in FIG. 6;

FIG. 9 shows an example of a needle for use in the apparatus of thepresent invention. View (a) shows the primary bevel face of the needle,view (b) shows the needle rotated by 90° about its longitudinal axiscompared with view (a), and view (c) shows the needle rotated about itslongitudinal axis by 180° compared with view (a).

FIG. 10 shows another example of a needle for use in the apparatus ofthe present invention. View (a) shows the primary bevel face of theneedle, view (b) shows the needle rotated by 90° about its longitudinalaxis compared with view (a), and view (c) shows the needle rotated aboutits longitudinal axis by 180° compared with view (a).

FIG. 11 shows another example of a needle for use in the apparatus ofthe present invention. View (a) shows the primary bevel face of theneedle, view (b) shows the needle rotated by 90° about its longitudinalaxis compared with view (a), and view (c) shows the needle rotated aboutits longitudinal axis by 180° compared with view (a).

FIG. 12 shows an example of a needle according to the present invention.View (a) shows the primary bevel face of the needle, and view (b) showsthe needle rotated by 90° about its longitudinal axis compared with view(a).

FIG. 13 shows a method of manufacturing a needle according to thepresent invention.

FIG. 14 shows another method of manufacturing a needle according to thepresent invention.

FIG. 15 shows a further method of manufacturing a needle according tothe present invention.

In a first variant of the injection apparatus according 30 to thepresent invention, as shown in FIG. 4, the injection apparatus 1comprises an upper portion 2 and a lower portion 4. The lower portionmay constitute or include a marker unit in certain example embodiments.The lower portion comprises a circular plate 6 having a central hole 8defined by a cylindrical boss 10 with an aperture 12. The upper portion2 is dome-shaped, and has a lower surface 14 which lies on the uppersurface 16 of the lower portion 4. The upper portion 2 has a centralcylindrical boss 18 extending downwards inside the boss 10 of the lowerportion 4. The rim 20 of the upper portion boss 18 is attached by apivot 22 to a skin positioning member constituted by a base plate 24 ofa bell crank 26. The base plate 24 occupies the central hole 8 of thelower portion 4. The lower surface 28 of the lower portion 4 and thelower surface 30 of the base plate 24 have an adhesive covering 32, 10which is covered with a release tape 34.

The upper portion 2 comprises a syringe 36 mounted in a cylindricalsleeve 38 at an angle of approximately 20° to the lower surface 14 ofthe upper portion 2. The sleeve 38 forms an integral part of a wedgeshaped block 39. The sleeve 38 has an axial slot 41 on its uppersurface. The syringe 36 comprises a syringe body 40, a needle housing 42and a plunger 44. The needle housing 42 extends from the lower end 46 ofthe syringe body 40, and comprises a collapsible sleeve 48 housing aneedle 50 which is attached to the syringe body 40. At its distal end 52the needle housing 42 passes through the aperture 12 and lies inside achamber 54 defined by the lower portion boss 10, and is sealed with anend cap 56. The plunger 44 lies in the upper end 58 of the syringe body40. The syringe body 40 contains material to be injected. In analternative variant, the double chamber syringes described below may beused.

The upper portion 62 of the bell crank 26 forms a cam follower 64. Camfollowers 66, 68, 70 are also mounted on the syringe body, the syringeplunger and the end cap respectively and protrude through the slot 41 inthe sleeve 38. Each of the cam followers 64, 66, 68, 70 is constrainedto radial movement in the direction 71.

A grooved cam plate 72 engages the cam followers 64, 66, 68, 70 to forma box cam. A cam groove 74 engaging cam follower 64 is initially angledto the left and then runs straight outwards towards the periphery of theapparatus 1. Cam grooves 76, 78 engaging cam followers 66, 68 initiallyrun parallel to the final portion of the cam groove 74, then are angledto the left with the cam groove 78 engaging cam follower 68 more steeplyangled, then parallel to the final portion of the cam groove 74. A camgroove 80 engaging cam follower 70 runs parallel to the final portion ofthe cam groove 74. The cam grooves 76, 78, 80 engaging cam followers 66,68, 70 terminate in a common lateral cam groove 82 which isperpendicular to the final portions of the cam grooves 76, 78, 80. Aspring (not shown) urges the cam followers 66, 68, 70 to the right. Thecam plate 72 is mounted on runners 84 such that it is constrained toslide forwards and backwards in the direction 85 only. The cam plate 72is attached on its upper surface 73 to a boss 87 which engages amanually engageable slider 86 on the upper surface 88 of the upperportion 2.

In use, the release tape 34 is removed from the adhesive covering 32 ofthe lower portion lower surface 28 and the bell crank base plate lowersurface 30. The adhesive lower surface 28, 30 is applied to the skin. Asmall area of skin 90 becomes adhesively attached to the bell crank baseplate 24, and an annular area of skin 92 surrounding the small area ofskin 90 becomes adhesively attached to the lower portion 4.

To effect injection, the manually engageable slider 86 is pushed acrossthe upper surface 88 of the upper portion 2 by the user. This causes thecam plate 72 to move forward along the runners 84 from its initialposition shown in FIG. 6 to a final position. As the cam plate 72 moves,the cam follower 64 of the bell crank 26 is immediately moved to theleft by the cam groove 74. This causes the bell crank 26 to rotatearound the pivot 22, such that the base plate 24 of the bell crank 26and the adhesively attached small area of skin 90 tilt relative to thelower surface 28 of the lower portion 4 to an angle of approximately20°.

As the plate 72 continues to move forward, the cam follower 66 on thesyringe body 40 is moved to the left by its cam groove 76. This causesthe syringe needle 50 to move through the end cap 56 and into thechamber 54 defined by the lower portion boss 10, collapsing the needlehousing 42. The needle 50 extends parallel to the lower surface 30 ofthe bell crank base plate 24 at a defined distance from it, such that itextends under the small area of skin 90 parallel to the skin surface ata defined depth. The depth may for example be 100 μm, which lies in thedermis just below the junction with the epidermis. In an alternativeembodiment, the distance between the bell crank base plate 24 and theneedle 50 (and hence the depth of injection) may not be preset inmanufacture but may be set by the user within a certain range, forexample using a dial coupled to a screw jack lifting the needleassembly.

Simultaneously, the cam follower 68 on the syringe plunger is moved tothe left by its cam groove 78. The steeper angle of this cam groove 78compared with the cam groove 76 for cam follower 66 means that thesyringe plunger 44 moves to the left relative to the syringe body 40 andtravels down the syringe body 40. This causes the material 60 to beinjected to be expelled through the needle 50 into the skin.

When the plate 72 reaches its final position, the cam followers 66, 68,70 are forced to the right in the lateral groove 80 by the spring (notshown), retracting the syringe 36 into its sleeve 38. The syringe 36 isnow shorter in length because the needle housing 42 has collapsed, andtherefore the syringe 36 does not protrude into the chamber 54 definedby the boss 10. The upper portion 2 of the injection apparatus 1 canthus be removed from the skin surface. It is necessary to remove theadhesive coating 32 from the lower surface 30 of the bell crank baseplate 24 to achieve this.

The lower portion 4 of the injection apparatus 1 is left adhesivelyattached to the annular area of skin 92. Its central hole 8 is used todefine the site of injection. This may be important, for example in theinjection of assays which need to be interrogated optically or otherwiseat the site of injection.

The needle for use in the above-described injection apparatus, inaccordance with the first and fourth aspects of the invention, has a tipwhich is closer to the longitudinal axis of the needle than is theoutside of the shaft of the needle. One way of achieving this is to bendthe needle tip towards the longitudinal axis of the needle. Such aneedle is commercially available as a Huber tip needle, for example fromwww.harvardapparatus.com. The bent needle may also be provided withsuitable shaping at the point. For example, as shown in FIG. 9, theneedle 310 may be of the form of a lancet-type needle, having a primarybevel face 320 and secondary bevels 330 formed at equal and oppositerotational angles about the longitudinal axis of the needle. The shapingmay be provided by any conventional means, such as grinding of theneedle with an abrasive surface such as a whetstone. The tip of theneedle may be bent towards the longitudinal axis after the secondarybevels have been formed, as shown in FIG. 9. Alternatively, the tip maybe bent before the secondary bevels are formed, as shown in FIG. 10.

A second method of making the needle tip closer to the longitudinal axisthan is the outside of the needle shaft is to provide additional shapingof the tip of the needle by suitable means such as grinding with anabrasive surface. The known trocar-type needle is an example of the useof such additional shaping, and the shape of the point of this type ofneedle tip is shown in FIG. 2. This type of needle has a primary bevel420, and two secondary bevels 440, each formed at a rotational angleabout the longitudinal axis of needle 410 of 120° to each other and tothe primary bevel. It is seen from the Figure that the tip 450 of theneedle 410 is thus formed closer to the longitudinal axis of the needlethan is the outside of the shaft of the needle.

Alternatively or additionally, at least one grinding may be formed atthe tip of the needle in order to make the tip closer to thelongitudinal axis. For example, a single grinding 560 may be formed at arotational angle of 180° to the primary bevel 520, which grinding 560 isinclined from the outside of the needle shaft towards the longitudinalaxis of the needle.

An additional grinding as described above may be advantageously be addedto a trocar needle. While not necessarily resulting in an adjustment ofthe tip position relative to the longitudinal axis, the additionalgrinding removes the sharp front edge of the tip of a standard trocarneedle that may split the skin surface when the needle is insertedparallel thereto. An example of such a needle is shown in FIG. 11, andis described in U.S. Pat. No. 5,968,022.

An alternative needle type advantageous in the injection methods andapparatuses of the second and fifth aspects of the present invention isa needle according to the third aspect of the invention in which thelength of the lumen opening of the needle is in a range from 5 to 15times the diameter of the shaft of the needle.

The intention in using such a needle is to reduce the asymmetry andapparent gauge of the needle and thereby reduce forces perpendicular tothe skin surface during forming of the injection channel. This in turnreduces the propensity of the needle to bend when being inserted intothe skin, and thus minimises the deviation of the needle from theintended injection path.

In order to achieve the above, the point of the needle, is formed byfurther shaping in order to remove part of the needle shaft and exposethe lumen of the needle, resulting in a part-cylindrical portion. Thisshaping also includes the creation of a further bevel immediately distalof the heel of the needle in order to facilitate the expansion of thechannel formed by the needle tip to accommodate the diameter of theshaft of the needle. Thus, when the channel has been formed by thepart-cylindrical portion of the point, it is then expanded to the fulldiameter of the needle tube by the insertion of the further bevel inorder that the injection of the desired material may be carried out. Twoplanes at different angles to the longitudinal axis (though at the samerotational angle about the longitudinal axis) may therefore be providedby the further shaping in order to form a stepped bevel face. Agraduated transition may be provided between the part-cylindricalsection and the further bevel, such as a curved transition, or there maybe a sharp angle formed between the part-cylindrical portion and thefurther bevel.

It is possible to envisage the manufacture of such a needle in a numberof ways. For convenience, the description of the manufacture of theneedle will be described starting from a lancet needle of known type.However, it will be appreciated that other types of needle, such as atrocar needle or a plain needle with a single bevel and no furthershaping of the point, may be used as a suitable starting point, or thatthe needle point may be shaped into the desired form, such as a trocaror lancet point, after the shaping described below has been carried out.The proximal end of the lumen opening of the needle may additionally beshaped in a known manner, such as by dulling the edge to prevent coring.This needle design may in principle be applied to any size of needle. Itis envisaged that such needles for use in intradermal injection willhave a shaft diameter in the range of 0.5 to 1.5 mm.

Referring to FIG. 12, two depictions of a needle according to thepresent invention are shown (elevation: FIG. 12(b); plan: FIG. 12(a)).The needle 610 depicted has a tip 620 shaped as for a known lancetneedle, having a primary bevel and two secondary bevels as describedabove. A standard lancet needle has secondary bevels whose lengths 340(FIG. 1), 680 (FIG. 12) are in the range from 2 to 2.5 times thediameter of the needle shaft. The point 630 of the needle extends fromthe tip 620 to the heel 640 and includes the whole of the tip and theheel. The lumen opening 625 extends from the tip 620 to the proximal endof the lumen opening 645, distal of the heel. The length of the lumenopening of the needle may be in the range of from 5 to 15 times thediameter of the needle shaft, for example 8 to 12 times, such as 10times the diameter of the needle shaft. Thus, for a needle forintradermal injection having a 1.1 mm shaft diameter (19G), the lengthof the lumen opening may be from 5.5 mm to 16.5 mm, for example 8.8 mmto 13.2 mm, such as 11 mm. The shaft 650 comprises the whole of theneedle proximal of the heel. It can be seen that a section of the needlehas been removed from point 630, forming a part-cylindrical portion, andexposing the lumen of the needle at 660.

The shaping of the point at 660 and/or the bevel 670 (proximal of 660and distal of heel 640) may be achieved by grinding the needle using arotating grinding stone having its axis of rotation parallel to thelongitudinal axis of the needle. Such an arrangement is shown in FIG.13. Where this method is used, the curvature of the surface of thegrinding stone determines the shaping of the needle at the transitionbetween the part-cylindrical portion and the further bevel of theneedle. For example, a rounded edge of the grinding stone will result ina rounded transition, whereas a chamfered edge will result in acorresponding chamfered transition.

Alternatively, the shaping of the point at 660 and/or the further bevel670 may be achieved by grinding the needle using a rotating grindingstone having its axis of rotation perpendicular to the longitudinal axisof the needle. Such an arrangement is shown in FIG. 14. Where thismethod is used, the diameter of the grinding stone is selected toachieve the required shape of the transition between thepart-cylindrical portion and the further bevel 670. The grinding stonemay also be used to shape the further bevel 670 to the required angle θto the longitudinal axis of the needle.

As a further alternative, the shaping of the point at 660 and thefurther bevel 670 may be achieved by wire erosion of the needle. Such anarrangement is depicted in FIG. 15. The shape of the point of the needleis defined by the path cut by the wire through the needle. Suitably, thepath of the wire may be substantially in the plane of the longitudinalaxis at 660, and at a desired angle θ to the longitudinal axis to formthe further bevel 670. At 660 it is envisaged that the wire may be movedin a path at an angle e-x to the longitudinal axis, so that the apparentdiameter of the needle increases gradually from the tip towards theheel. Suitably, the angle θ may be 10°, and the angle x may be between 0and θ, such as 0 to 5°. Preferably, however, the part-cylindricalportion of the needle is formed by moving the wire parallel to thelongitudinal axis of the needle (i.e. at an angle θ−x=0), as thisarrangement minimises the component of the reaction forces actingperpendicular to the injection path during insertion of the needle intothe skin.

These preferred embodiments of the injection apparatus allow injectionto a fixed depth to be achieved accurately. The system has severaladvantages over prior art methods of injection. First, as the needleextends under the skin surface the site of entry of the needle is notnear the site of injection. This may be important in opticalinterrogation of assays. Secondly, the channel depth of the needle inthe skin is much larger than the injection depth. This means that a sealis formed between the skin and the needle, so that the material to beinjected does not travel along the outside of the needle to the outsideof the skin. Thirdly, injected material is often spread out because ofthe pressure of injection and the possibility of migration throughtissue. This is particularly significant in vertical injection into theskin, where material often reaches the fat tissue below the skin whichhas a low resistance to flow. Using the present injection apparatus,even if the injected material is spread out, it will be spreadhorizontally at the same depth. When the apparatus is used to injectassay sensors, this has the advantage that there is no stray signal fromsensors at depths other than the required depth.

Further, the use of the needles described herein in conjunction with thedescribed injection apparatuses allows the depth of injection to bereliably reproduced, particularly when injecting substances or particlesrequiring a large lumen diameter needle to be used. A particularapplication for which this advantage is important is the implantation ofsensor particles in the skin in order to carry out measurement of bloodglucose concentration based on fluorescence lifetime spectroscopy, asthe sensor must be placed immediately below the basement membrane whichseparates the dermis from the epidermis in order that the sensor maymeasure the glucose concentration in a vasculised region of the skin andthat the sensor may be optically interrogated.

In an alternative embodiment, the tiltable base plate 24 may be replacedby an inclined surface which is pressed against the skin surface toprovide a fixed-depth injection path parallel to the inclined surface.The inclined surface may be the surface of a cone, the apex of the conebeing pressed against the skin surface, or may be the surface of a flatplate pressed at an angle against the skin.

FIGS. 4 and 7 show a double chamber syringe 94 suitable for use with apreferred embodiment of the invention. This syringe 94 is used forinjecting powder suspended in a liquid 98 which is kept separate fromthe powder 96 until the moment of injection. In alternative embodiments,the syringe may contain a liquid and two powders, two liquids and apowder, a solid dose and a liquid, a solid dose and a plunger, or othermaterials to be injected. Such a syringe is described in detail inWO003/072172.

Whilst the invention has been described with reference to theillustrated embodiments, it is to be appreciated that many modificationsand variations are possible within the scope of the invention.

The invention claimed is:
 1. An injection apparatus for making aninjection at a predetermined depth in skin, comprising: a skinpositioning member for positioning a patch of skin within an area ofskin to hold the patch of skin in a defined position; an injectionneedle comprising a tip, at least one bevel and a heel together forminga point at a distal end thereof, and a shaft portion immediatelyproximal of said heel having a longitudinal axis, including a lumenextending along the longitudinal axis, wherein the at least one bevel isformed between said tip and said heel such that a lumen opening isdefined from the tip to a proximal end of the lumen opening locateddistal of the heel; and an injection needle movement guide proximate theinjection needle to guide said injection needle for movement from aparking position above said skin positioning member to an injectionposition in which the distal end of the needle lies at a predetermineddistance below said skin positioning member; wherein: a length of thelumen opening of the needle from the tip of the needle to the proximalend of the lumen opening is in a range from 5 to 15 times an outerdiameter of the shaft of the needle and the length of the lumen openingof the needle is measured parallel to the longitudinal axis of theneedle; wherein at least a part of the point of the injection needle isformed substantially parallel to the longitudinal axis of the needle. 2.The injection apparatus according to claim 1, further comprising ahousing containing: the injection needle mounted for guided movementfrom a parked position to an operative position; a detachable markerunit mounted to said housing and so positioned that said needle passestherethrough to reach said operative position; and a securing membercoupled to the marker unit to secure said marker unit at an injectionsite prior to the making of an injection, whereby said apparatus can inuse be positioned at an injection site, said needle can be moved to saidoperative position to make an injection and said housing can be removedleaving said marker unit at the injection site to mark the positionthereof.
 3. The injection apparatus according to claim 2, wherein saidmarker unit comprises a plate having an aperture therein through whichthe needle passes in use.
 4. The injection apparatus according to claim3, wherein said aperture has a maximum dimension of 2 mm or less.
 5. Theinjection apparatus according to claim 1, wherein the tip of theinjection needle is closer to the longitudinal axis of the shaft portionthan is the outside of the shaft portion.
 6. The injection apparatusaccording to claim 1, in which the outer diameter of the shaft of theinjection needle is between 0.5 mm to 1.5 mm.
 7. The injection apparatusaccording to claim 1, in which the outer diameter of the shaft of theinjection needle is 1.1 mm.
 8. The injection apparatus according toclaim 1, in which the length of the lumen opening of the injectionneedle is between 5.5 mm and 16.5 mm.
 9. The injection apparatusaccording to claim 1, in which at least a part of the point of theinjection needle is in the form of a part-cylinder.
 10. The injectionapparatus according to claim 9, in which the distance perpendicular tothe longitudinal axis of the injection needle from the tip to the bevelface at the part-cylinder is at least 50% of the outer diameter of theshaft of the needle.
 11. The injection apparatus according to claim 1,wherein the distal end of the needle lies within the skin.
 12. Theinjection apparatus according to claim 1, wherein the length of thelumen opening of the needle is in a range from 8 to 12 times an outerdiameter of the shaft of the needle.
 13. The injection apparatusaccording to claim 9, further comprising a second bevel, wherein thebevel and the second bevel are on opposite longitudinal ends of thepart-cylinder and the bevel and the second bevel are formed at similarangles with respect to the longitudinal axis.
 14. An injection apparatusfor making an injection at a predetermined depth in skin comprising: askin positioning member for positioning on a patch of skin within anarea of skin to hold the patch of skin in a defined position, aninjection needle comprising a point having a tip at a distal end thereofand a shaft portion immediately proximal to said point, the shaftportion having a longitudinal axis, and an injection needle movementguide proximate the injection needle to guide said injection needle formovement from a parking position above the skin beside said skinpositioning member to slide beneath said skin positioning member to aninjection position in which the distal end of the needle lies at apredetermined distance below said skin positioning member; wherein: thetip of the injection needle is closer to the longitudinal axis of theshaft portion than is an outside of the shaft portion; wherein the tipof the injection needle is closer to the longitudinal axis of the shaftportion than is the outside of the shaft by bending the tip of theinjection needle.